Effects of endotoxin upon rat hepatic microsomal drug metabolism in vivo and in vitro

1. Bacterial endotoxin, a soluble lipopolysaccharide, has been studied to ascertain its effects in vivo and in vitro on the hepatic drug-metabolizing enzymes of adult male and female rats.2. 24h after a single 1–0 or 2–0mg/kg i.p. dose of endotoxin, hexobarbital sleeping time was significantly increased in adult male rats. Significant inhibition of liver microsomal cytochrome P-450 occurred after 6 h and continued only until 24 h after endotoxin administration, while injection of inactivated endotoxin did not result in any significant decrease of hepatic mixed-function oxidase enzymes or cytochrome P-450. In contrast, p-nitrophenol-UDP-glucuronyltransferase enzyme activity was unaffected by these levels of endotoxin.3. Electron-microscopic examination of rat liver hepatocytes did not reveal any significant change in ultrastructure 24h after a single i.p. dose of endotoxin.4. Endotoxin failed to depress the phenobarbitone- or 3-methylcholanthrene-induced forms of cytochrome P-450 and the dependent mono-oxy...